Identification of novel drug targets for multiple sclerosis by integrating plasma genetics and proteomes

• Published in: Experimental gerontology Vol. 194; p. 112505
• Main Authors: Liu, Yi, Wang, Qian, Zhao, Yuhui, Liu, Liu, Hu, Jingxi, Qiao, Yao, Chen, Jinyi, Qin, Chao
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.09.2024; Elsevier
• Subjects: Bayesian colocalization; Genome-wide association studies; Mendelian randomization; Multiple sclerosis; Proteome-wide association studies; Multiple sclerosis; Genome-wide association studies; GWAS; FUSION; MR; MS; IVs; CNS; Mendelian randomization; pQTL; TWAS; Proteome-wide association studies; Bayesian colocalization; SNPs; DGIdb; PWAS
• ISSN: 0531-5565; 1873-6815; 1873-6815
• DOI: 10.1016/j.exger.2024.112505

Genome-wide association studies (GWAS) have revealed numerous loci associated with multiple sclerosis (MS). However, the challenge lies in deciphering the mechanisms by which these loci influence the target traits. Here, we employed an integrative analytical pipeline to efficiently transform genetic associations to identify novel proteins for MS. We systematically integrated MS GWAS data (N = 115,803) with human plasma proteome data (N = 7213) and conducted proteome-wide association studies (PWAS) to identify MS-associated pathogenic proteins. Following this, we employed Mendelian randomization and Bayesian colocalization analyses to verify the causal relationship between these significant plasma proteins and MS. Lastly, we utilized the Drug-Gene Interaction Database (DGIdb) to identify potential drug targets for MS. The PWAS identified 25 statistically significant cis-regulated plasma proteins associated with MS at a false discovery rate of P < 0.05. Further analysis revealed that the abundance of 7 of these proteins (PLEK, TNXB, CASP3, CD59, CR1, TAPBPL, ATXN3) was causally related to the incidence of MS. Our findings indicated that genetically predicted higher levels of TNXB and CD59 were associated with a lower risk of MS, whereas higher levels of PLEK, CASP3, CR1, TAPBPL, and ATXN3 were associated with an increased risk of MS. Three plasma proteins (PLEK, CR1, CD59) were validated by colocalization analysis. Among these, CR1 was prioritized as a target for Eculizumab due to its significant association with MS risk. Additionally, PLEK, CR1, and CD59 were identified as druggable target genes. Our proteomic analysis has identified PLEK, CR1, and CD59 as potential drug targets for MS treatment. Developing pharmacological inducers or inhibitors for these proteins could pave the way for new therapeutic approaches, potentially improving outcomes for MS patients. [Display omitted] •GWAS has found many MS risk loci, but deciphering the mechanisms is challenging.•We employed an integrative analytical pipeline to identify novel plasma proteins for MS.•Three proteins were identified as compelling proteins (i.e., PLEK, CR1, and CD59).•These proteins may offer insights for MS research and potential diagnostic targets.